Emerging Novel Treatments for Severe Mood Disorders Involving Cellular Plasticity Cascades

Mood disorders are the most prevalent psychiatric disorders. Despite recent advances in the understanding of therapeutically relevant biochemical pathways associated with mood regulation, patients with bipolar disorder and major depression present high rates of recurrences, residual symptoms, and pharmacologic refractoriness. Increasing evidence supports the observations that mood disorders are accompanied by regional brain volumetric reductions accompanied by cellular atrophy/loss. In this paper, we review and critique the data suggesting that neurotrophic signaling cascades may play a role in the pathophysiology and treatment of mood disorders. This suggests that effective treatments will need to provide both trophic and neurochemical support, which serves to enhance and maintain normal synaptic connectivity, thereby allowing the chemical signal to reinstate optimal functioning of critical circuits necessary for normal affective functioning. For many refractory patients, drugs mimicking "traditional" strategies, which directly or indirectly alter monoaminergic levels, may be of limited benefit. Newer "plasticity enhancing" strategies that may have utility in the treatment of mood disorders include inhibitors of glutamate release, NMDA antagonists, AMPA potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid receptor antagonists.